AIDS AT 20

AIDS AT 20; On Research Frontier, Basic Questions

Published: June 5, 2001

Correction Appended

(Page 3 of 3)

Now Dr. Jay Levy and his colleagues at the University of California at San Francisco are joining the study, recruiting 40 more patients. But the work is still highly preliminary, the investigators caution.

''We want to be sure people understand that we don't have data yet to show we've had a clinical benefit,'' Dr. Walker said. And, he added, the patients were unusual because almost all were found within a month of being infected with H.I.V.

''We are in no way recommending that people do this on their own, under any circumstances. This is definitely not something that's ready for people to try on their own or with their own doctor.''

Jim H. says he is one of the lucky ones. The AIDS drugs gave him terrible diarrhea and he hated the regimented schedule of taking them. ''It was just a complete change of life,'' he said. He stopped taking them in August and, so far at least, his immune system is able to keep the virus in check. He comes in once a month for tests to see if the virus is still being squelched.

''It's not a cure,'' said Jim, who still is infected with H.I.V. ''It's like God gave me a break.''

The Mystery

Experts Try to Find Virus's Hiding Place

Just a few years ago, many AIDS experts thought they had the virus on the run. When they gave patients a combination of drugs, the AIDS drug cocktail, the number of viruses in the blood fell to levels so low that they were undetectable.

''There were proposals that it would be possible to eliminate the infection,'' said Dr. Robert Siliciano, an AIDS researcher at the Johns Hopkins medical school. ''It was hoped that eradication would be possible.''

Then reality set in.

Dr. Martin Markowitz, the clinical director of the Aaron Diamond AIDS Research Center in New York, told scientists at a recent AIDS meeting what happened when 14 patients stopped taking their AIDS drugs.

They had begun taking drugs, on average, two months after the virus first entered their bodies -- much later than the patients in Dr. Walker's study -- and had taken the drugs for about three to six years. But, Dr. Markowitz said, as soon they stopped, the virus came roaring back.

That leaves a mystery -- if the drugs are so effective, where is the virus coming from? Along with the work on early treatment, the search for the virus's hiding places is one of the most provocative areas in the frontier of AIDS research, medical experts say.

The answer to the question of where the virus hides can determine if AIDS can ever be cured. If there is a virus reservoir that can be attacked -- perhaps by surgically removing the infected tissue or finding drugs that home in on it -- maybe doctors can one day rid people of H.I.V. for good. But if the reservoir is inaccessible, a cure may not be possible.

Dr. Siliciano, for one, holds out little hope of eradicating the H.I.V. reservoir, even if a person is treated early. People like Bob Massey or Jim H., he says, are like people who have had chickenpox. The virus is still there -- just hiding -- and their immune system keeps it in check. In the case of chickenpox, the virus hides for a lifetime in nerve cells, tamped down by the immune system when it tries to re-emerge.

One place H.I.V. hides, Dr. Siliciano said, is in a tiny fraction of the helper T-cells themselves. The virus inserts its genes among the cell's own genes, lurking silently and invisibly.

''It's latent, it's totally hidden, it is not seen by the immune system. It is stable and it is in a cell that is designed to live essentially for life,'' Dr. Siliciano said. ''And you can never remove the viral genetic material.''

Only about one in a million of this subset of helper cells, a group known as memory cells, contain H.I.V. genes, Dr. Siliciano finds. But that is enough to start an infection anew, putting patients who do not have the immune defense of Bob Massey or Jim H. in a bind. As soon as they stop taking the antiviral drugs, the virus can take over and proliferate unabated.

Dr. Siliciano is trying to find ways to flush the virus out of the memory T-cells, but he is not optimistic. ''We think this mechanism guarantees that H.I.V. will stay around indefinitely,'' he said.

But others say that while the memory cells may be a source of the virus, they cannot be the whole story of the H.I.V. reservoir.

Dr. Malcolm Martin, the chief of the laboratory of molecular microbiology at the National Institute of Allergy and Infectious Diseases, began questioning the hypothesis when he looked at monkeys infected with a potent form of an AIDS virus. Within a month, the virus destroys every T-cell in the animal's body. Six months later, the animals die.

''A light bulb went off,'' Dr. Martin said. Every T-cell was gone. But the virus was coming from somewhere because the monkeys' blood contained as many as 10 million viruses in every drop. Where, then, are they coming from? he asked.

He finds the virus in another class of immune system cells, the macrophages, which protect the body by engulfing and consuming bacteria, dying cells, cancer cells and cells that are infected with microorganisms.

''We've known for going on 20 years that macrophages do get infected quite early,'' Dr. Martin said. ''But people have overlooked them.''

One reason is that macrophages are hard to study. ''You have to pull them out of tissue, you have to grind up tissue and then culture them under conditions that keep them happy,'' he said. ''We can't do that very well.''

The AIDS viruses in macrophages apparently do not kill the cells, and the viruses inside them are impervious to the AIDS drugs that are now on the market, Dr. Martin added. ''Once you have a macrophage infected, it might produce virus until kingdom come,'' Dr. Martin said.

But Dr. Stephen O'Brien, an AIDS researcher at the National Cancer Institute in Frederick, Md., noted that while the virus might be in memory T-cells and macrophages and other body cells, that did not prove that these cells were the source of the virus that sprang back whenever a patient stopped taking AIDS drugs. And so, he asks, ''Where are the engines, where are the factories that are making the virus?''

His plan is to search for the factories with tools used to study origins of species. If, for example, scientists want to know the history of a species with numerous subspecies, like the leopards of Asia, North Africa, Central Africa and South Africa, they may look at the genetic profiles of the animals and build evolutionary trees. The idea is to find a genetic pathway that can lead from a common ancestor to the leopards seen today by means of a few genetic changes.

''Suppose you consider the human body as the world, the whole ecosystem,'' Dr. O'Brien said. ''The AIDS virus comes into all these tissues. The immune system kills it in some tissues, but not in others.'' And as it moves from tissue to tissue, it divides and mutates, creating a path that may be traced back to its origins. Might it be possible, he asks, to reconstruct the virus's evolutionary history -- and find the H.I.V. factory -- within the body by examining the genes of viruses from different tissues?

He is now starting to analyze the virus in different tissues taken from patients in autopsies. These are people who are part of the Multicenter AIDS Cohort Study, a collaborative study that began in the early 1980's and has been following several thousand gay men.

It is far too early to know if the approach will succeed, Dr. O'Brien said. And, of course, the project is an expensive gamble since it may turn out that the virus mutates so quickly or so slowly that it is impossible to trace its path.

But, Dr. O'Brien adds, he has reason to hope: ''We're very encouraged by what we're seeing.''

Photos: Dr. Bruce Walker, left, draws blood from Robert Massey, who has been infected with H.I.V. for 23 years. (Rick Friedman for The New York Times)(pg. F1); Dr. Robert Siliciano examines an H.I.V. culture in his laboratory at Johns Hopkins. Dr. Janet Siliciano works with her husband in the lab. (Michelle Gienow); Dr. Martin Markowitz, of the Aaron Diamond AIDS Research Center in New York, has studied patients who stopped taking their AIDS drugs. (Ruth Fremson/The New York Times)(pg. F9) Chart: ''Where Can the AIDS Virus Hide?'' Drugs can reduce the presence of H.I.V. to undetectable levels, but it remains hidden, ready to roar back. Scientists suspect that two types of white blood cells, HELPER T-CELLS and MACROPHAGES, are among its refuges. Ordinarily, helper T-cells can direct other cells in the body's immune system, and macrophages consume infected cells. HIDING IN BLOOD AND LYMPHATIC SYSTEM H.I.V. injects its genetic material, RNA, into a helper T-cell. The RNA is used to make DNA, which is inserted into the cell's DNA where it can remain hidden only to revive itself in the future. HIDING IN TISSUE When an infected T-cell is engulfed by a macrophage, the degenerating T-cell leaves behind DNA from the virus that can integrate with the macrophage's DNA, remaining hidden. Like a T-cell, a macrophage can also be infected directly by H.I.V. Diagrams of Helper T-Cell and Macrophage (Source: Dr. Malcolm A. Martin, N.I.H.)(pg. F9)

Correction: June 9, 2001, Saturday An article and a picture caption in Science Times on Tuesday about progress in AIDS research misspelled the surname and misstated the age of a man with hemophilia who has been infected for 23 years with H.I.V. He is Robert Massie, not Massey. He is 44, not 46.